In our current investigations we first verified that the significant symptom reductions reported by Raynaud's disease patients given temperature feedback (TEMP) and temperature feedback under cold stress (TEMPCS) were maintained over a 3-year, follow-up period and that the TEMPCS group maintained its superiority over the TEMP group. We then demonstrated that a beta-adrenergic vasodilating mechanism is active during temperature feedback and that capillary blood flow is significantly increased during feedback in patients but not normals. We now propose to determine if any of the effects of temperature feedback are neurally mediated, to see if these effects generalize to the lower extremities, and to determine if increased capillary blood flow is responsible for the long-term effects of TEMP and TEMPCS treatment and for the continued superiority of the latter. If TEMPCS treatment promotes increased capillary blood flow over extended time periods, it may be beneficial in the treatment of Raynaud's phenomenon in scleroderma. We propose to test this in a controlled study, using an isotope clearance procedure implemented during the past year. Recently, an increased number of Alpha2 receptors has been reported on the platelets of patients with idiopathic Raynaud's disease. We, therefore, propose to examine finger vascular responses to arterial infusion of clonidine, a selective Alpha2 agonist. Also, evidence exists that norepinephrine (NE) released from sympathetic nerve endings may produce vascular effects different from those of exogenously administered catecholamines or synthetic agonists. Tyramine acts by liberating stored NE from adrenergic nerve endings and we propose to compare the digital vascular responses to tyramine of Raynaud's disease patients and matched normals. Finally, research on the etiology of Raynaud's disease has been hindered by the inability to produce attacks in the laboratory. Recently, Wise et al. reported induction of attacks in 100% of 14 Raynaud's patients using total body cooling. We propose to employ this procedure to examine the role of the sympathetic nerves in vasospastic attacks using selective digital nerve blocks.